ID PR15A_MOUSE Reviewed; 657 AA. AC P17564; Q3TJS6; Q3U3L5; Q8C579; DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot. DT 01-AUG-1990, sequence version 1. DT 15-FEB-2017, entry version 117. DE RecName: Full=Protein phosphatase 1 regulatory subunit 15A; DE AltName: Full=Growth arrest and DNA damage-inducible protein GADD34; DE AltName: Full=Myeloid differentiation primary response protein MyD116; GN Name=Ppp1r15a; Synonyms=Gadd34, Myd116; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Sciurognathi; OC Muroidea; Muridae; Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC STRAIN=SL; RX PubMed=2339071; DOI=10.1093/nar/18.9.2823; RA Lord K.A., Hoffman-Liebermann B., Liebermann D.A.; RT "Sequence of MyD116 cDNA: a novel myeloid differentiation primary RT response gene induced by IL6."; RL Nucleic Acids Res. 18:2823-2823(1990). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2). RC STRAIN=C57BL/6J, and NOD; TISSUE=Cerebellum, and Placenta; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., RA Davis M.J., Wilming L.G., Aidinis V., Allen J.E., RA Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., RA Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., RA Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., RA Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., RA di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., RA Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., RA Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., RA Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., RA Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., RA Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., RA Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., RA Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., RA Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., RA Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., RA Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., RA Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., RA Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., RA Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., RA Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., RA Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., RA Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., RA Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., RA Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., RA Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., RA Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., RA Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., RA Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., RA Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., RA Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., RA Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [3] RP INDUCTION. RX PubMed=8139541; DOI=10.1128/MCB.14.4.2361; RA Zhan Q., Lord K.A., Alamo I. Jr., Hollander M.C., Carrier F., Ron D., RA Kohn K.W., Hoffman B., Liebermann D.A., Fornace A.J. Jr.; RT "The gadd and MyD genes define a novel set of mammalian genes encoding RT acidic proteins that synergistically suppress cell growth."; RL Mol. Cell. Biol. 14:2361-2371(1994). RN [4] RP INTERACTION WITH PCNA. RX PubMed=9371605; RA Brown S.M., MacLean A.R., McKie E.A., Harland J.; RT "The herpes simplex virus virulence factor ICP34.5 and the cellular RT protein MyD116 complex with proliferating cell nuclear antigen through RT the 63-amino-acid domain conserved in ICP34.5, MyD116, and GADD34."; RL J. Virol. 71:9442-9449(1997). RN [5] RP INTERACTION WITH PP1. RX PubMed=9023344; DOI=10.1073/pnas.94.3.843; RA He B., Gross M., Roizman B.; RT "The gamma(1)34.5 protein of herpes simplex virus 1 complexes with RT protein phosphatase 1alpha to dephosphorylate the alpha subunit of the RT eukaryotic translation initiation factor 2 and preclude the shutoff of RT protein synthesis by double-stranded RNA-activated protein kinase."; RL Proc. Natl. Acad. Sci. U.S.A. 94:843-848(1997). RN [6] RP FUNCTION, INTERACTION WITH PP1, AND MUTAGENESIS OF VAL-549. RX PubMed=11381086; DOI=10.1083/jcb.153.5.1011; RA Novoa I., Zeng H., Harding H.P., Ron D.; RT "Feedback inhibition of the unfolded protein response by GADD34- RT mediated dephosphorylation of eIF2alpha."; RL J. Cell Biol. 153:1011-1022(2001). RN [7] RP INTERACTION WITH LYN. RX PubMed=11517336; DOI=10.1073/pnas.191130798; RA Grishin A.V., Azhipa O., Semenov I., Corey S.J.; RT "Interaction between growth arrest-DNA damage protein 34 and Src RT kinase Lyn negatively regulates genotoxic apoptosis."; RL Proc. Natl. Acad. Sci. U.S.A. 98:10172-10177(2001). RN [8] RP INDUCTION, AND FUNCTION. RX PubMed=12606582; DOI=10.1093/emboj/cdg112; RA Novoa I., Zhang Y., Zeng H., Jungreis R., Harding H.P., Ron D.; RT "Stress-induced gene expression requires programmed recovery from RT translational repression."; RL EMBO J. 22:1180-1187(2003). RN [9] RP FUNCTION, INDUCTION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND RP DISRUPTION PHENOTYPE. RX PubMed=12824288; DOI=10.1096/fj.02-1184fje; RA Kojima E., Takeuchi A., Haneda M., Yagi A., Hasegawa T., Yamaki K., RA Takeda K., Akira S., Shimokata K., Isobe K.; RT "The function of GADD34 is a recovery from a shutoff of protein RT synthesis induced by ER stress: elucidation by GADD34-deficient RT mice."; RL FASEB J. 17:1573-1575(2003). RN [10] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=16478986; DOI=10.1128/MCB.26.5.1644-1653.2006; RA Patterson A.D., Hollander M.C., Miller G.F., Fornace A.J. Jr.; RT "Gadd34 requirement for normal hemoglobin synthesis."; RL Mol. Cell. Biol. 26:1644-1653(2006). RN [11] RP FUNCTION, AND INDUCTION. RX PubMed=17670836; DOI=10.1128/JVI.01063-07; RA Minami K., Tambe Y., Watanabe R., Isono T., Haneda M., Isobe K., RA Kobayashi T., Hino O., Okabe H., Chano T., Inoue H.; RT "Suppression of viral replication by stress-inducible GADD34 protein RT via the mammalian serine/threonine protein kinase mTOR pathway."; RL J. Virol. 81:11106-11115(2007). CC -!- FUNCTION: Recruits the serine/threonine-protein phosphatase PP1 to CC dephosphorylate the translation initiation factor eIF-2A/EIF2S1, CC thereby reversing the shut-off of protein synthesis initiated by CC stress-inducible kinases and facilitating recovery of cells from CC stress. Down-regulates the TGF-beta signaling pathway by promoting CC dephosphorylation of TGFB1 by PP1. May promote apoptosis by CC inducing TP53 phosphorylation on 'Ser-15'. In case of infection CC with vesicular stomatitis virus (VSV), impairs viral replication. CC {ECO:0000269|PubMed:11381086, ECO:0000269|PubMed:12606582, CC ECO:0000269|PubMed:12824288, ECO:0000269|PubMed:16478986, CC ECO:0000269|PubMed:17670836}. CC -!- SUBUNIT: Interacts with KMT2A/MLL1. Interacts with SMARCB1. CC Interacts with SMAD7. Interacts with BAG1 (By similarity). CC Interacts with PCNA. Interacts with LYN. Interacts with PP1 and CC PPP1R1A. {ECO:0000250, ECO:0000269|PubMed:11381086, CC ECO:0000269|PubMed:11517336, ECO:0000269|PubMed:9023344, CC ECO:0000269|PubMed:9371605}. CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Peripheral CC membrane protein; Cytoplasmic side {ECO:0000250|UniProtKB:O75807}. CC Mitochondrion outer membrane; Peripheral membrane protein; CC Cytoplasmic side {ECO:0000250|UniProtKB:O75807}. Note=Associates CC with membranes via an N-terminal amphipathic intramembrane region. CC {ECO:0000250|UniProtKB:O75807}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P17564-1; Sequence=Displayed; CC Name=2; CC IsoId=P17564-2; Sequence=VSP_031651; CC -!- TISSUE SPECIFICITY: Expressed strongly in spleen and lung, CC moderately in thymus and muscle, and weakly in brain. CC {ECO:0000269|PubMed:12824288}. CC -!- DEVELOPMENTAL STAGE: Expression starts at E8.5, and decreases to CC undetectable levels at E10.5 and E11.5. Expression is strongly up- CC regulated at E12.5, decreases at E16.5 and reappears at E18.5. At CC E12.5, ubiquitously expressed, with high levels in brain, spinal CC cord, tongue, lung and genital tubercle. CC {ECO:0000269|PubMed:12824288}. CC -!- INDUCTION: By IL6 and various endoplasmic stresses such as methyl CC methanesulfonate. By infection with various viruses such as CC vesicular stomatitis virus (VSV). {ECO:0000269|PubMed:12606582, CC ECO:0000269|PubMed:12824288, ECO:0000269|PubMed:17670836, CC ECO:0000269|PubMed:8139541}. CC -!- PTM: Phosphorylated at multiple Ser/Thr residues. Phosphorylated CC on tyrosine by LYN; which impairs its antiproliferative activity. CC Phosphorylation at Tyr-239 enhances proteasomal degradation, this CC position is dephosphorylated by PTPN2. CC {ECO:0000250|UniProtKB:O75807}. CC -!- PTM: Polyubiquitinated. Exhibits a rapid proteasomal degradation CC with a half-life under 1 hour, ubiquitination depends on CC endoplasmic reticulum association. {ECO:0000250|UniProtKB:O75807}. CC -!- DISRUPTION PHENOTYPE: Mice display abnormal erythrocytes and CC reduced hemoglobin content due to defects in hemoglobin synthesis. CC {ECO:0000269|PubMed:12824288, ECO:0000269|PubMed:16478986}. CC -!- SIMILARITY: Belongs to the PPP1R15 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X51829; CAA36128.1; -; mRNA. DR EMBL; AK079339; BAC37613.1; -; mRNA. DR EMBL; AK154697; BAE32770.1; -; mRNA. DR EMBL; AK167317; BAE39419.1; -; mRNA. DR CCDS; CCDS21249.1; -. [P17564-1] DR PIR; S10001; S10001. DR RefSeq; NP_032680.1; NM_008654.2. [P17564-1] DR UniGene; Mm.4048; -. DR ProteinModelPortal; P17564; -. DR SMR; P17564; -. DR BioGrid; 201637; 2. DR STRING; 10090.ENSMUSP00000049488; -. DR iPTMnet; P17564; -. DR PhosphoSitePlus; P17564; -. DR PaxDb; P17564; -. DR PRIDE; P17564; -. DR Ensembl; ENSMUST00000042105; ENSMUSP00000049488; ENSMUSG00000040435. [P17564-1] DR Ensembl; ENSMUST00000167273; ENSMUSP00000128497; ENSMUSG00000040435. [P17564-1] DR GeneID; 17872; -. DR KEGG; mmu:17872; -. DR UCSC; uc009gvt.3; mouse. [P17564-1] DR CTD; 23645; -. DR MGI; MGI:1927072; Ppp1r15a. DR eggNOG; ENOG410ITE6; Eukaryota. DR eggNOG; ENOG410Y1YJ; LUCA. DR GeneTree; ENSGT00510000049287; -. DR HOGENOM; HOG000060154; -. DR HOVERGEN; HBG052542; -. DR InParanoid; P17564; -. DR KO; K14019; -. DR OMA; VRAWVYR; -. DR OrthoDB; EOG09040GSJ; -. DR PhylomeDB; P17564; -. DR TreeFam; TF105547; -. DR PRO; PR:P17564; -. DR Proteomes; UP000000589; Chromosome 7. DR Bgee; ENSMUSG00000040435; -. DR CleanEx; MM_MYD116; -. DR ExpressionAtlas; P17564; baseline and differential. DR Genevisible; P17564; MM. DR GO; GO:0005737; C:cytoplasm; ISO:MGI. DR GO; GO:0005783; C:endoplasmic reticulum; ISO:MGI. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI. DR GO; GO:0016020; C:membrane; ISO:MGI. DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005739; C:mitochondrion; ISO:MGI. DR GO; GO:0000164; C:protein phosphatase type 1 complex; ISO:MGI. DR GO; GO:0019901; F:protein kinase binding; ISO:MGI. DR GO; GO:0008157; F:protein phosphatase 1 binding; ISO:MGI. DR GO; GO:0019903; F:protein phosphatase binding; IDA:ParkinsonsUK-UCL. DR GO; GO:0019888; F:protein phosphatase regulator activity; IDA:ParkinsonsUK-UCL. DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW. DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IMP:MGI. DR GO; GO:1903912; P:negative regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:0032515; P:negative regulation of phosphoprotein phosphatase activity; ISO:MGI. DR GO; GO:0035308; P:negative regulation of protein dephosphorylation; ISO:MGI. DR GO; GO:1903573; P:negative regulation of response to endoplasmic reticulum stress; IDA:ParkinsonsUK-UCL. DR GO; GO:1990441; P:negative regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress; IDA:ParkinsonsUK-UCL. DR GO; GO:0070262; P:peptidyl-serine dephosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:1903917; P:positive regulation of endoplasmic reticulum stress-induced eIF2 alpha dephosphorylation; ISO:MGI. DR GO; GO:0010628; P:positive regulation of gene expression; IDA:ParkinsonsUK-UCL. DR GO; GO:1902310; P:positive regulation of peptidyl-serine dephosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:0032516; P:positive regulation of phosphoprotein phosphatase activity; ISO:MGI. DR GO; GO:0045943; P:positive regulation of transcription from RNA polymerase I promoter; IDA:ParkinsonsUK-UCL. DR GO; GO:0070972; P:protein localization to endoplasmic reticulum; ISO:MGI. DR GO; GO:0060734; P:regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation; IDA:ParkinsonsUK-UCL. DR GO; GO:0036496; P:regulation of translational initiation by eIF2 alpha dephosphorylation; ISO:MGI. DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:ParkinsonsUK-UCL. DR InterPro; IPR019523; Prot_Pase1_reg-su15A/B_C. DR Pfam; PF10488; PP1c_bdg; 1. PE 1: Evidence at protein level; KW Alternative splicing; Apoptosis; Complete proteome; KW Endoplasmic reticulum; Membrane; Mitochondrion; KW Mitochondrion outer membrane; Phosphoprotein; Reference proteome; KW Repeat; Stress response; Translation regulation; Ubl conjugation. FT CHAIN 1 657 Protein phosphatase 1 regulatory subunit FT 15A. FT /FTId=PRO_0000096665. FT TOPO_DOM 1 21 Cytoplasmic. FT {ECO:0000250|UniProtKB:O75807}. FT INTRAMEM 22 39 Helical. {ECO:0000250|UniProtKB:O75807}. FT TOPO_DOM 40 657 Cytoplasmic. FT {ECO:0000250|UniProtKB:O75807}. FT REPEAT 283 322 1. FT REPEAT 323 360 2. FT REPEAT 361 398 3. FT REPEAT 399 436 4. FT REPEAT 437 451 5; truncated. FT REGION 1 60 Required for localization in the FT endoplasmic reticulum. FT {ECO:0000250|UniProtKB:O75807}. FT REGION 283 451 4.5 X approximate repeats. FT REGION 323 503 Interaction with SMAD7. {ECO:0000250}. FT REGION 443 548 Interaction with KMT2A/MLL1. FT {ECO:0000250}. FT REGION 529 576 Interaction with SMARCB1. {ECO:0000250}. FT COMPBIAS 455 458 Poly-Glu. FT MOD_RES 239 239 Phosphotyrosine. FT {ECO:0000250|UniProtKB:O75807}. FT MOD_RES 368 368 Phosphotyrosine. FT {ECO:0000250|UniProtKB:O75807}. FT MOD_RES 406 406 Phosphotyrosine. FT {ECO:0000250|UniProtKB:O75807}. FT MOD_RES 505 505 Phosphotyrosine. FT {ECO:0000250|UniProtKB:O75807}. FT VAR_SEQ 284 360 Missing (in isoform 2). FT {ECO:0000303|PubMed:16141072}. FT /FTId=VSP_031651. FT MUTAGEN 549 549 V->E: Abolishes interaction with PP1. FT {ECO:0000269|PubMed:11381086}. FT CONFLICT 224 224 P -> H (in Ref. 2; BAE39419). FT {ECO:0000305}. FT CONFLICT 271 271 E -> G (in Ref. 2; BAE32770). FT {ECO:0000305}. FT CONFLICT 505 505 Y -> C (in Ref. 2; BAE32770). FT {ECO:0000305}. SQ SEQUENCE 657 AA; 71840 MW; 9B217001019C38A7 CRC64; MAPSPRPQHV LHWRDAHNFY LLSPLMGLLS RAWSRLRGPE VPEAWLAKTV TGADQIEAAA LLTPTPVSGN LLPHGETEES GSPEQSQAAQ RLCLVEAESS PPETWGLSNV DEYNAKPGQD DLREKEMERT AGKATLQPAG LQGADKRLGE VVAREEGVAE PAYPTSQLEG GPAENEEDGE TVKTYQASAA SIAPGYKPST PVPFLGEAEH QATEEKGTEN KADPSNSPSS GSHSRAWEYY SREKPKQEGE AKVEAHRAGQ GHPCRNAEAE EGGPETTFVC TGNAFLKAWV YRPGEDTEEE DNSDSDSAEE DTAQTGATPH TSAFLKAWVY RPGEDTEEED SDSDSAEEDT AQTGATPHTS AFLKAWVYRP GEDTEEENSD LDSAEEDTAQ TGATPHTSAF LKAWVYRPGE DTEEENSDLD SAEEDTAQTG ATPHTSPFLK AWVYRPGEDT EDDTEEEEDS ENVAPGDSET ADSSQSPCLQ PQRCLPGEKT KGRGEEPPLF QVAFYLPGEK PESPWAAPKL PLRLQRRLRL FKAPTRDQDP EIPLKARKVH FAEKVTVHFL AVWAGPAQAA RRGPWEQFAR DRSRFARRIA QAEEKLGPYL TPDSRARAWA RLRNPSLPQS EPRSSSEATP LTQDVTTPSP LPSETPSPSL YLGGRRG //